as) United States
`a2) Patent Application Publication co) Pub. No.: US 2008/0085922 Al
`Apr.10, 2008
`Raja et al.
`(43) Pub. Date:
`
`US 20080085922A1
`
`METHODS AND OPHTHALMIC DEVICES
`USED IN THE TREATMENT OF OCULAR
`ALLERGIES
`
`(22)
`
`Filed:
`
`Mar. 16, 2007
`
`Related U.S. Application Data
`
`(54)
`
`(76)
`
`Inventors: Ranganath R. Raja, Jacksonville, FL
`(US); Shivkumar Mahadevan, Orange
`Park, FL (US); Azaam Alti,
`Jacksonville, FL (US); Frank F.
`Molock, Orange Park, FL (US); Brain
`Pall, Jacksonville, FL (US)
`
`Correspondence Address:
`PHILIP S. JOHNSON
`JOHNSON & JOHNSON
`ONE JOHNSON & JOHNSON PLAZA
`
`NEW BRUNSWICK, NJ 08933-7003 (US)
`
`(21)
`
`Appl. No.:
`
`—-11/686,979
`
`(60)
`
`Provisional application No. 60/848,332, filed on Sep.
`29, 2006.
`
`Publication Classification
`
`61)
`
`Int. Cl.
`
`(2006.01)
`AG6LK 31/44
`(2006.01)
`A6IP 27/02
`US. C1. ieee secs cssesneseesescsscensseseeneeees 514/324
`
`ABSTRACT
`
`(52)
`
`(57)
`
`Ophthalmic devices and methods of treating allergic con-
`junctivitis are disclosed herein.
`
`
`
`
`
`KetotifenReleased(%)
`
`Percent Ketotifen Released from K-Lenses (Ex-Vivo)
`
`100
`
`coSo
`
`a>So
`
`EoS
`
`ROoS
`
`0
`
`30
`
`60
`90
`Time (minutes)
`
`120
`
`150
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1029, Page 1
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1029, Page 1
`
`

`

`Patent Application Publication Apr. 10, 2008
`
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`IPR2018-01020 and IPR2018-01021, Exhibit 1029, Page 2
`
`

`

`US 2008/0085922 Al
`
`Apr. 10, 2008
`
`limited to chemical substances that inhibit the release of
`
`histamine, that block the binding of histamine to its recep-
`tors, inhibit mast cell production. Additional anti-allergic
`agents include but are not limited to decongestants, non-
`steroidal anti-inflammatory compound, and steroidal com-
`pounds. Particularly,
`examples of anti-allergic
`agents
`include but are not
`limited to acetmetacin, acrivastine,
`aldosterone, antazoline, astemizole, azatadine, azelastine,
`beclometasone, betamethasone, bromfenac, buclizine, car-
`profen, cetirizine, chloropyriline, chloropheniramine, clem-
`astine, cromolyn, cyclizine, cyproheptadine, dexametha-
`sone, diazoline, diclofenac, diphenhydramine, ebastine,
`emedastine, epinastine, etodolac, fenbufen, fenoprofen, fex-
`ofenadine,
`fludrocortisone,
`flurbiprofen,
`flurometalone,
`hydroxyzine, ibuprofen, indometacin, ketoprofen, ketorolac
`tromethamine,
`ketotifen,
`levocabastine,
`levoceterizine,
`lodoxamide,
`loratadine,
`loteprednol,
`loxoprofen,
`medrysone, mepivacaine, mequitazine, methdilazine, meth-
`apyrilene, nabumetone, naphazoline, naproxen, nedocromil,
`norastemizole, norebastine, olopatadine, phenidamine, phe-
`nylephrine, oxatamide, oxymetazoline, pemirolast, phe-
`niramine, picumast, prednisilone, promethazine, rimexa-
`lone,
`repirinast,
`sulindac,
`suprofen,
`tetrahydozoline,
`terfenadine, tiaprofenic acid, tometim, tranilast, triamcino-
`lone,
`trimeprazine,
`triprolidine,
`and pharmaceutically
`acceptable salts and mixtures thereof. Preferred anti-allergic
`agent include acrivatine, antazoline, astemizole, azatadine,
`azelastine, clemastine, cyproheptadine, ebastine, emedas-
`tine, fexofenadine, hydroxyzine, ketotifen,
`levocabastine,
`levoceterizine, mequitazine, methdialazine, methapyrilene,
`norastemizole, norebastine, picumast, promethazine,
`ter-
`fenadine, trimeprazine,
`triprolidine, and pharmaceutically
`acceptable salts and mixtures thereof. The class of sub-
`stances known as antihistamines are the particularly pre-
`ferred anti- allergic agents The particularly preferred anti-
`histamines
`include,
`azelastine,
`epinastine,
`ketotifen,
`ketotifen fumarate, nor-ketotifen fumarate, olopatadine and
`mixtures thereof. Moreparticularly preferred antihistamines
`include ketotifen, its pharmaceutically acceptable salts and
`mixtures thereof.
`
`METHODS AND OPHTHALMIC DEVICES USED
`IN THE TREATMENT OF OCULAR ALLERGIES
`
`RELATED APPLICATIONS
`
`[0001] This application claims priority from a non-provi-
`sional filing, U.S. application patent Ser. No. 60/848,332
`which wasfiled on Sep. 29, 2006.
`
`FIELD OF THE INVENTION
`
`[0002] This invention related to devices and treatments for
`allergic conjunctivitis.
`
`BACKGROUND
`
`[0003] Allergic conjunctivitis is a disease of the eye that
`affects millions of people. The symptoms of this disease
`include itchiness, tearing, and swelling of the eyes. Some-
`times this disease is seasonally associated with the spring
`and summerhay fever seasons, but many people experience
`symptoms of this disease throughout the year. The symp-
`tomsof allergic conjunctivitis are caused and mediated by
`the binding of histamine to its receptor. Antihistamines are
`a class of pharmaceutical agent known to either or both
`suppress the release of histamine from associated mast cells
`and prevent
`the binding of histamine to its associated
`receptors. These agents have been usedto treat the symp-
`toms ofallergic conjunctivitis and one such agent is keto-
`tifen fumarate. Topical solutions of ketotifen fumarate are
`currently sold in the United States. The concentration keto-
`tifen in of the U.S. approved ketotifen fumarate formulation
`is 0.025% (0.25 mg/mL). At that concentration, the recom-
`mended dosing regimen is twice daily. It is known that the
`recommended dosing can be reduced if the amount of
`ketotifen fumarate is increased, but it is also known that
`higher concentrations of ketotifen fumarate sting and burn
`upon initial administration to the eye.
`
`[0004] Further it is known that they symptomsofallergic
`conjunctivitis have a greater impact on the wearers of
`contact lenses. Many contact lens wearers stop using their
`lenses during the spring and summerhay fever seasons and
`other peak allergen seasons. Contact
`lens wearers can
`administer topical ketotifen solutions to reduce the symp-
`toms of allergic conjunctivitis. However, if the inconve-
`nience of carrying a bottle of solution can be avoided, it
`would be beneficial. In addition, since it is knownthat higher
`concentrations of the ketotifen fumarate can cause stinging
`and burning,
`it would be beneficial if the symptoms of
`allergic conjunctivitis were alleviated by administering an
`amount of ketotifen fumarate to patients that did not cause
`stinging in a dose that lasts longer than 6 hours. These
`benefits are provided by the following invention.
`
`[0007] The term “minimum effective amount” refers to the
`weight of anti-allergic agent contained in an ophthalmic
`device prior to its use by a patient wherein such minimum
`effective amount alleviates the symptomsof allergic con-
`junctivitis. The minimum effective amount may vary
`depending upon the efficacy of a particular anti-allergic
`agent. For example, if the anti-allergic agent is ketotifen
`fumarate, the minimum effective amount is between greater
`than about 9 ug and aboutless than 90 ug, more particularly
`between about 40 pg and greater than about 9 ug, most
`preferably about for 20 ug. It is preferred that minimum
`effective amount of anti-allergic agent other than ketotifen
`fumarate is an amountthat exhibits an efficacy equivalent to
`or more efficacious greater than about 9 ug and aboutless
`[0005] FIG.1illustrates the ex-vivo release of ketotifen.
`than 90 ug, more particularly between about 40 ug and about
`9 ug of ketotifen fumarate.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0006] This invention includes an ophthalmic device com-
`prising about a minimum effective amountof an anti-allergic
`agent. As used herein “anti-allergic agent” refers to chemical
`substancesthat alleviate the symptomsofallergic conjunc-
`tivitis. While not wishing to be bound by any particular
`mechanism ofaction, anti-allergic agents include but are not
`
`It is preferred that the minimum effective amount
`[0008]
`of anti-allergic agent alleviates the symptomsof allergic
`conjunctivitis for between about 5 minutes, and about 24
`hours from insertion of the ophthalmic device into the eye of
`a user, more preferably between about 5 minutes and about
`16 hours, most preferably between about 5 minutes and
`about 12 hours.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1029, Page 3
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1029, Page 3
`
`

`

`US 2008/0085922 Al
`
`Apr. 10, 2008
`
`[0009] As used herein, “ophthalmic device” refers to an
`object that resides in or on the eye. These devices can
`provide optical correction or may be cosmetic. Ophthalmic
`devices include but are not limited to soft contact lenses,
`intraocular lenses, overlay lenses, ocular inserts, punctual
`plugs, and optical inserts. The preferred ophthalmic devices
`of the invention are soft contact lenses made from silicone
`
`elastomers or hydrogels, which include but are notlimited to
`silicone hydrogels, and fluorohydrogels and excludes oph-
`
`thalmic devices that contain phosphate group-containing
`methacrylates
`(ie. CH,—C(CH,)—C(O)—(CH,),—_O
`P(O)(OH),, where n is 1-4; CH,C—C(CH,)—C(O)—
`(CH,),—O—P(O)(OH)—O—(CH,),-O—C(O)—
`C(CH,)—CH.,) or pre-polymers as such defined by USPat.
`Application Publication No. US 2006/0100408. Soft contact
`lens formulations are disclosed in U.S. Pat. No. 5,710,302,
`WO 9421698, EP 406161, JP 2000016905, U.S. Pat. No.
`5,998,498, U.S. Pat. No. 6,087,415, U.S. Pat. No. 5,760,100,
`USS. Pat. No.5,776, 999, U.S. Pat. No. 5,789,461, U.S. Pat.
`No. 5,849,811, and U.S. Pat. No. 5,965,631. The foregoing
`references are hereby incorporated by reference in their
`entirety. The particularly preferred ophthalmic devices of the
`inventions are prepared from formulations known by the
`United States Approved Namesof acofilcon A, alofilcon A,
`alphafilcon A, amifilcon A,astifilcon A, atalafilcon A, bala-
`filcon A, bisfilcon A, bufilcon A, comfilcon, crofilcon A,
`cyclofilcon A, darfilcon A, deltafilcon A, deltafilcon B,
`dimefilcon A, drooxifilcon A, epsifilcon A, esterifilcon A,
`etafilcon A, focofilcon A, galyfilcon A, genfilcon A, gova-
`filcon A, hefilcon A, hefilcon B, hefilcon D, hilafilcon A,
`hilafilcon B, hioxifilcon B, hioxifilcon C, hixoifilcon A,
`hydrofilcon A,
`lenefilcon A,
`licryfilcon A,
`licryfilcon B,
`lidofilcon A, lidofilcon B, lotrafilcon A, lotrafilcon B, mafil-
`con A, mesifilcon A, methafilcon B, mipafilcon A, nelfilcon
`A, netrafilcon A, ocufilcon A, ocufilcon B, ocufilcon C,
`ocufilcon D, ocufilcon E, ofilcon A, omafilcon A, oxyfilcon
`A, pentafilcon A, perfilcon A, pevafilcon A, phemfilcon A,
`polymacon, senofilcon A, silafilcon A, siloxyfilcon A,tefil-
`con A, tetrafilcon A, trifilcon A, vasurfilcon, vifilcon, and
`xylofilcon A. More particularly preferred ophthalmic
`devices of the invention are genfilcon A,
`lenefilcon A,
`comfilcon, lotrafilcon A, lotraifilcon B, and balafilcon A.
`More preferred lenses include comfilcon, etafilcon A, galy-
`filcon A, senofilcon A, nelfilcon A, hilafilcon, tetrafilcon A,
`vasurfilcon, vifilcon, and polymacon. The most preferred
`lenses include etafilcon A.
`
`[0010] Further the invention includes a method ofallevi-
`ating the symptoms of allergic conjunctivitis comprising
`administering to a patient an ophthalmic device comprising
`about a minimum effective amountof an anti-allergic agent.
`The terms ophthalmic device, minimum effective amount
`and anti-allergic agent all have their aforementioned mean-
`ings and preferred ranges. As used herein, the term “admin-
`istering” means placing the ophthalmic device of the inven-
`tion onto the surface of the eye, or in the eye, of a patient.
`If the device is in contact with the anterior surface of the
`
`patient’s eye, such as a soft contact lens, it is preferred that
`the ophthalmic device remain in contact with that surface for
`between about 5 minutes, and about 24 hours from insertion
`of the ophthalmic device into the eye of a user, more
`preferably between about 5 minutes and about 16 hours,
`more preferably between about 5 minutes and about 12
`hours, most preferably between about 5 minutes and greater
`than about 12 hours. If the ophthalmic device is contained
`
`within the eye or on the ocular adnexa, such as a punctual
`plug or an ocular insert,it is preferred that the device remain
`in contact with the eye for at least 24 hours.
`
`Still further the invention includes a method of
`{0011]
`making an ophthalmic device comprising about a minimum
`effective amount of an anti-allergic agent comprising the
`step of treating an ophthalmic device with a solution com-
`prising said anti-allergic agent, wherein the amount of said
`anti-allergic agent in said solution exceeds the minimum
`effective amount. It is preferred that the minimum effective
`amount
`is exceeded by between about 1.0% and about
`1000%,in a volumeofsolution that is between about 500 pL
`and about 5000 uL preferably between about 50% and about
`500%, in a volumeofsolution that is between about 500 uL
`and about 3000 uL most preferably about 50% in a volume
`of solution that is about 1000 uL.
`
`[0012] As used herein treating means physical methods of
`contacting the solution containing an anti-allergic agent and
`the ophthalmic device. Preferably treating refers to physical
`methods of contacting the anti-allergic agent with the oph-
`thalmic devices prior to selling or otherwise delivering the
`ophthalmic devices to a patient. The ophthalmic devices
`maybetreated with the anti-allergic agent anytimeafter they
`are polymerized. Polymerization refers to the process in
`which components of an ophthalmic device including but
`not limited to monomers, pre-polymers, diluents, catalysts,
`initiators, tints, UV blockers, antibacterial agents, polymer-
`ization inhibitors, and the like are reacted by thermal,
`chemical, and light initiated curing techniques to produce a
`formed polymer. The preferred methods of polymerization
`are the light initiated techniques disclosed in U.S. Pat. No.
`6,822,016 which is hereby incorporated by reference in its
`entirety. It
`is preferred that the polymerized ophthalmic
`devices be treated with anti-allergic agent at temperature of
`greater than about 50° C. For example in some processes to
`manufacture contact lenses, an un-polymerized, or partially
`polymerized formulation is placed between two mold
`halves, spincasted, or static casted and polymerized. See,
`US. Pat. Nos. 4,495,313; 4,680,336; 4,889,664, 3,408.429;
`3,660,545; 4,113,224; and 4,197,266, all of which are incor-
`porated by reference in their entirety. In the case of hydro-
`gels, the ophthalmic device formulation is a hardened disc
`that is subjected to a number ofdifferent processing steps
`including treating the polymerized ophthalmic device with
`liquids (such as water, inorganic salts, or organic solutions)
`to swell, or otherwise equilibrate this polymerized oph-
`thalmic device prior to enclosing the polymerized oph-
`thalmic device in its final packaging. Polymerized oph-
`thalmic devices that have not been swelled or otherwise
`equilibrated are known as un-hydrated polymerized oph-
`thalmic devices. The addition of the anti-allergic agent to
`any of the liquids of this “swelling” or “equilibrating” step
`at room temperature or below is considered “treating” the
`lenses with anti-allergic agent as contemplated by this
`invention. In addition, the polymerized un-hydrated oph-
`thalmic devices may be heated above room temperature with
`the anti-allergic agent during swelling or equilibrating steps.
`The preferred temperature range is from about 50° C. for
`about 15 minutes to about
`sterilization conditions as
`described below, more preferably from about 50° C. to about
`85° C. for about 5 minutes.
`
`[0013] Examplesofblister packages andsterilization tech-
`niques are disclosed in the following references which are
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1029, Page 4
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1029, Page 4
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`

`

`US 2008/0085922 Al
`
`Apr. 10, 2008
`
`hereby incorporated by reference in their entirety, U.S. Pat.
`Nos. D435,966; 4,691,820; 5,467,868; 5,704,468; 5,823,
`327; 6,050,398, 5,696,686; 6,018,931; 5,577,367; and
`5,488,815. This portion of the manufacturing process pre-
`sents another methodoftreating the ophthalmic devices with
`anti-allergic agent, namely adding anti-allergic agents to a
`solution prior to sealing the package, and subsequently
`sterilizing the package. This is the preferred method of
`treating ophthalmic devices with anti-allergic agents.
`
`[0014] Sterilization can take place at different tempera-
`tures and periods of time. The preferred sterilization condi-
`tions range from about 100° C. for about 8 hours to about
`150° C. for about 0.5 minute. More preferred sterilization
`conditions range from about 115° C. for about 2.5 hours to
`about 130° C. for about 5.0 minutes. The most preferred
`sterilization conditions are about 124° C. for about 18
`minutes.
`
`[0015] The “solutions” that are used in methods of this
`invention may be water-based solutions. Typical solutions
`include, without limitation, saline solutions, other buffered
`solutions, and deionized water. The preferred aqueous solu-
`tion is deionized water or saline solution containing salts
`including, without
`limitation,
`sodium chloride,
`sodium
`borate,
`sodium phosphate,
`sodium hydrogenphosphate,
`sodium dihydrogenphosphate, or the corresponding potas-
`sium salts of the same. These ingredients are generally
`combinedto form buffered solutions that include an acid and
`
`its conjugate base, so that addition of acids and bases cause
`only a relatively small change in pH. The buffered solutions
`may additionally include 2-(N-morpholino)ethanesulfonic
`acid (MES), sodium hydroxide, 2,2-bis(hydroxymethyl])-2,
`2',2"-nitrilotriethanol, n-tris(hydroxymethyl)methyl-2-ami-
`noethanesulfonic acid, citric acid, sodium citrate, sodium
`carbonate, sodium bicarbonate, acetic acid, sodium acetate,
`ethylenediamine tetraacetic acid and the like and combina-
`tions thereof. Preferably, the solution is a borate buffered or
`phosphate buffered saline solution or deionized water. The
`particularly preferred solution contains about 500 ppm to
`about 18,500 ppm sodium borate, most particularly pre-
`ferred about 1000 ppm of sodium borate.
`
`If the anti-allergic agents are subject to oxidative
`[0016]
`degradation, agents that stabilize solutions containing such
`anti-allergic agents may be added. Such “oxidative stabili-
`zation agents” include butare not limited to chelants such as
`EDTA, Dequest, Desferal, silica, chitin derivatives such as
`chitosan, cellulose and its derivatives, and N,N,N',N',N",
`N"-hexa(2-pyridyl)-1,3,5-tris(aminomethyl)benzene,
`and
`certain macrocyclic ligands such as crown ethers,
`ligand
`containing knots and catenands. See, David A. Leigh et al
`Angew. Chem Int. Ed., 2001, 40, No. 8, pgs. 1538-1542 and
`Jean-Claude Chambronet al. Pure & Appl. Chem., 1990,
`Vol. 62, No. 6, pgs. 1027-1034. Oxidative stabilization
`agents may include other compoundsthat inhibit oxidations
`such as those selected from the group consisting of 2,2',2",
`6,6',6"-Hexa-(1,1-dimethylethyl)4,4',4"-[(2,4,6-trimethy1-1,
`3,5-benzenetriyl)-trismethylene]-triphenol (Irganox 1330),
`1,3, 5tris[3,5-di(1,1-dimethylethyl)4-hydroxybenzy1]-1H,
`3H,5H-1,3,5-triazine-2,4,6-trione, pentaerythrityl tetrakis[3-
`[3,5-di(1,1-dimethylethy1)-4-hydroxypheny1]-propionate],
`octadecyl1-3 -[3,5-di(1,1-dimethylethyl)-4-hydroxypheny]]-
`propionate,
`_tris[2,4-di(1,1-dimethylethy1)-phenyl]-phos-
`phite,
`2,2'-di(octadecyloxy)-5,5'-spirobi(1,3,2-dioxaphos-
`phorinane),
`dioctadecyl
`disulphide,
`didodecyl-3,3'-
`
`dioctadecy]-3,3'-thiodipropionate,
`thiodipropionate,
`butylhydroxytoluene, ethylene bis[3,3-di[3-(1,1-dimethyl-
`ethyl)-4-hydroxypheny]]butyrate] and mixtures thereof. The
`preferred oxidative stabilization agents are diethylenetri-
`aminepentaacetic acid (“DTPA”), or salts of DTPA such as
`CaNa,DTPA, ZnNa,DTPA, and Ca,DTPA.See, U.S. appli-
`cation patent No. 60/783,557 filed on, Mar. 17, 2006,
`entitled “Methods for Stabilizing Oxidatively Unstable
`Pharmaceutical Compositions” and its corresponding non-
`provisional filing which are hereby incorporated by refer-
`ence in their entirety. Therefore, the invention includes a
`method of preventing oxidation of an ophthalmic device
`comprising an anti-allergic agent, wherein the method
`includes treating said ophthalmic device with a solution
`comprising an oxidative stabilization agent. It is preferred
`that at the concentration of oxidative stabilization agents in
`the solution be from about 2.5 umoles/liter to about, 5000
`umoles/liter more preferably from about 20 umoles/liter to
`about 1000 umoles/liter, more preferably from about 100
`umoles/liter to about 1000 pmoles/liter, most preferably
`from about 100 umoles/liter to about 500 umoles/liter.
`
`[0017] Yet still further the invention includes an oph-
`thalmic device comprising about a localized amount of an
`anti-allergic agent. As used herein the terms anti-allergic
`agent and ophthalmic device have their afore mentioned
`preferred identities and preferred ranges.
`
`[0018] As used herein, the term “localized amount”refers
`to an amountof anti-allergic agent that located in discrete
`portions of the ophthalmic device. For example, the local-
`ized amount maybeonthe front or back surface (using those
`terms as applied to contact lenses) of the device, or in any
`otherarea or surface. It is preferred that the localized amount
`remain in contact with the conjunctiva of the eye when
`placed in the eye of a user. It is preferred that the localized
`amount of anti-allergic agent is between about
`1 tg and
`about 200 ug, preferably between about 1 ug and about 90
`ug, more preferably between about 1 wg and about 50 ug,
`most preferably between about 2 ug and about 20 ug. The
`anti-effective agent may be adding to a discrete area of the
`device by including the anti-allergic agent in coatings or
`pigments that may be added to the devices. See, U.S. Pat.
`Nos. 7,172,286; and 6,767,097, WO 02/057837, WO
`03/057837 U.S. Pat. App. Nos. US 2002/0133889, and US
`2003/0000028 coatings and pigments that may be applied to
`ophthalmic devices as well methods of applying the same to
`such devices
`
`[0019] Yet further still the invention includes a method of
`alleviating the symptomsofallergic conjunctivitis compris-
`ing administering to a patient an ophthalmic device com-
`prising about a localized amountofan anti-allergic agent. As
`used herein the terms anti-allergic agent, localized amount,
`and ophthalmic device have their afore mentioned preferred
`identities and preferred ranges.
`
`Still further, the invention includes a methodalle-
`[0020]
`viating the symptomsofallergic conjunctivitis in a patient
`for an extended period of time, wherein said method com-
`prises administering to the eye of said patient an adminis-
`tration system comprising said anti-allergic agent, wherein
`said administration system releases to said patient a dosing
`effective amount of an anti-allergic agent. The term anti-
`allergic
`agent has
`its
`aforementioned meaning. The
`“extended period of time”is from about 5 minutes to about
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1029, Page 5
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`greater than 24 hours depending upon the administration
`system. The term administration system refers to a physical
`object that contains an anti-allergic agent that releases the
`contained anti-allergic to the eye of a patient over time. The
`preferred administration systems are ophthalmic devices
`that are exposed to the anterior surface ofthe eye, in the eye,
`or on the ocular adnexa. Such preferred administrative
`systemsinclude soft contact lenses, punctual plugs or ocular
`inserts, most particularly,
`the soft contact
`lenses of this
`invention. If the administration system is a soft contact lens
`the preferred extended period of time is greater than about
`12 hours, more preferably between about 13 hours and about
`24 hours, most preferably between about 13 hours and about
`18 hours. If the administration system is a punctual plug or
`an ocular insert, the preferred period of time is greater than
`24 hours. The term “administering” means placing said
`administration system on or in the eye of a patient. The term
`“releases” means separating the anti-allergic agent from its
`administration system so that said anti-allergic agent
`is
`available to eye of a patient. If the ophthalmic device is
`administered to the anterior surface ofthe eye, it is preferred
`that the administration system release between about 10%
`and about 90% ofits contained anti-allergic agent between
`administering the device to the eye and about 60 minutes,
`more preferably between 10% and about 70% in about 30
`minutes. If the administration system does not contact the
`exterior surface of the eye and is placed in another portion
`of the eye, it is preferred that such administration system
`release its containedanti-allergic agent over a period of time
`equal to or greater than 24 hours. The term “dosing effective
`amount” refers to an amountofanti-allergic agent sufficient
`to alleviate the symptomsof allergic conjunctivitis for an
`extended period of time. This amount may vary depending
`upon the potency of the anti-allergic agent. For example if
`the ophthalmic device contains ketotifen, the preferred dos-
`age effective amount is between about less than 1 ug and
`about 20 wg. The preferred dosage effective amount
`is
`between aboutless than 1 wg and about 20 ug. It is preferred
`that the dosing effective amount of ketotifen released to the
`eye of a patient from about 1 minute to about 300 minutes.
`It is particularly preferred that between about 10% and about
`75% ofthe ketotifen contained within the ophthalmic device
`is delivered to the eye of a patient within about 60 minutes.
`
`In order to illustrate the invention the following
`[0021]
`examples are included. These examples do not limit the
`invention. They are meant only to suggest a method of
`practicing the invention. Those knowledgeable in contact
`lenses as well as other specialties may find other methods of
`practicing the invention. However,
`those methods are
`deemed to be within the scope of this invention.
`
`EXAMPLES
`
`Example 1
`
`Preparation of Ophthalmic Devices Containing 10
`ug and 25 wg of Ketotifen Fumarate
`
`[0022] To prepare 1000g ofa 10 pg/mL ketotifen fumarate
`(“K-10:
`
`[0023]
`
`1. 9.10 g of boric acid
`
`[0024]
`
`2. 1.00 g of sodium borate decahydrate
`
`[0025]
`
`3. 8.30 g of sodium chloride
`
`[0026]
`
`4. 0.10 ¢ of Ca2DTPA
`
`[0027]
`
`5. 981.49 g of deionized water
`
`[0028]
`
`6. 0.01 g of ketotifen fumarate
`
`[0029] The system is maintained at room temperature
`throughout the solution making process. All components 1-6
`are added in any order and stirred using a magnetic or
`mechanicalstirrer until the solution is homogeneous. Keto-
`tifen fumarate is added last and the mixtureis stirred for an
`
`additional 30 minutes or as long as it takes to make the
`solution homogeneous.
`
`[0030] The procedure to prepare a 25 ug/mL ketotifen
`fumarate solution is identical to that described above, with
`the only exceptions being the amount of ketotifen fumarate
`(0.025 g instead of 0.010 g) and water (981.475 g instead of
`981.49 g).
`
`1-Day Acuvue® Brand Contact Lenses (etafilcon
`[0031]
`A) were removed from their packages and repackaged in
`glass vials containing 3.0 mL of the 10 ug/mL or the 25
`ug/mL ketotifen fumarate solutions described above to pro-
`duce K-Lens 10 and K-Lens 25 respectively. The vials were
`sealed with PTFE coated rubber stoppers and heated for 18
`minutes at 124° C.
`
`Example 2
`
`Clinical Evaluation of Ophthalmic Devices of
`Example 1
`
`[0032] This was a single-center double-masked, random-
`ized, placebo controlled, clinical trial to assess the efficacy
`of the lenses of Example 1
`in a conjunctivial allergen
`challenge (CAC Model ). See, Netland et al, Emedastine
`Ophthalmic Solution 0.05% Versus Levocabastine Oph-
`thalmic Suspension 0.05% in the Treatment of Allergic
`Conjunctivitis Using the Conjunctival Allergen Challenge
`Model, American Journal of Ophthalmology VOL. 130, No.
`6, page 717-723, 718 for a description of a positive test to
`a CAC challenge. At the first visit (Day—2823), subjects
`underwent an allergen titration and a contact lensfitting.
`During the allergen titration, a CAC was performed bilat-
`erally with animal
`(cat) allergens, grass,
`tree, or wood
`pollens. Beginning with the lowest dose, one drop (25 uL)
`of solubilized allergen was instilled into the conjunctival
`cul-de-sac bilaterally. If the subject failed to react within 10
`minutes, increasing doses may have been instilled in both
`eyes at a minimum of ten minute intervals until a positive
`reaction waselicited. A positive CAC wasdefined as atleast
`Grade 2.0+ redness in both eyes in 2 of the 3 vessel beds
`(conjunctival, ciliary, and episcleral), and 2.0+ inching in
`both eyes, within 10 minutes of receiving that dose of
`allergen. Subjects were then be given an approved OTC
`antiallergy eye drop after all CAC evaluations were com-
`pleted to relieve any ocular itching or redness. Subjects were
`then fitted with placebo lenses. Lens fit was evaluated
`approximately 30 minutes after insertion. Subjects were then
`given a one week supply of placebo lenses with the instruc-
`tions to use on a daily basis.
`
`[0033] At the second visit (Study Day—143), subjects
`underwentan allergen titration with contact lenses. Subjects
`inserted a new set of placebo lenses in each eye. Subjects
`then underwent a CAC with one drop of allergen dilution
`one dose lower than previously determined at Visit
`1
`
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`instilled into each eye. If after 10 minutes the subject failed
`to react positively to the allergen (2Grade 2 redness and
`=2Grade 2 itching OU in 2 of the 3 vessel beds), the subject
`was re-challenged with a higher dose. Subjects were then
`given another week supply of daily wear contact lenses.
`
`[0034] At Visit 3 (Study Day—7+3), an allergen confir-
`mation was done. This visit also served as an untreated
`comparison visit. Subjects inserted a new set of placebo
`lenses in each eye. Subjects then underwent CAC with one
`drop of allergen dose previously determined at Visit 2 to
`have induced an allergic response instilled into each eye.
`Subjects evaluated ocular itching prior to CAC challenge
`and 3, 5, and 7 minutes following the allergen instillation.
`Investigators evaluated conjunctival, episcleral and ciliary
`hyperemia, chemosis and mucous discharge prior to the
`CAC challenge and 7, 15 and 20 minutes following the
`allergen instillation. Tearing and lid swelling were evaluated
`by the subject prior to CAC challenge and at 7, 15 and 20
`minutes post-challenge. Subjects were then given another
`week supply of daily wear contact lenses.
`
`[0035] Visit 4 evaluated the effectiveness of K-Lens solu-
`tion instilled 12 hours prior to CAC. Subjects were randomly
`assigned to one of five treatment groups: K-Lens 10/Pla-
`cebo, K-Lens 25/Placebo, K-Lens 10/K-Lens 10, K-Lens
`25/K-Lens 25, and Placebo/Placebo. For the contralateral
`eye subjects (K-Lens and placebo), the K-Lens was coun-
`terbalanced between the OD and OSeye. After inserting the
`assigned contact lens with the designated solution, subjects
`waited at the site for 30 minutes for a visual acuity exami-
`nation, slit lamp biomicroscopy, and lens fit evaluation.
`Subjects were then allowedto leave the office with instruc-
`tions to return 11 hours later. At 12 hours postlens insertion,
`subjects underwent CAC. Subjects evaluated ocular itching
`prior to CAC challenge and 3, 5, and 7 minutes following the
`allergen instillation. Investigators evaluated conjunctival,
`episcleral and ciliary hyperemia, chemosis, and mucous
`discharge prior to the CAC challenge and 7, 15 and 20
`minutes following the allergen instillation. Tearing and lid
`swelling were evaluated by the subject prior to the CAC
`challenge and at 7, 15 and 20 minutes post-challenge.
`Subjects were then given another two week supply of daily
`wear contact lenses.
`
`[0036] Visit 5 evaluated the effectiveness of K-Lens solu-
`tion instilled 8 hours prior to CAC. Subjects received the
`contact lenses in the samesolution that they received at Visit
`4. After inserting the assigned contactlens in the designated
`solution, subjects waited at the site for 30 minutes for a
`visual acuity examination, slit lamp biomicroscopy andlens
`fit evaluation. Subjects were then allowedto leave the office
`with instructions to return 7 hours later. At 8 hours post lens
`insertion, subjects underwent CAC. The sameallergy signs
`and symptoms evaluations done at Visit 4 were repeated at
`Visit 5.
`
`[0037] Eighty subject were enrolled and 79 completed the
`evaluation. Each enrolled subject was randomly assigned to
`one of five treatment groups:
`
`[0038] K-Lens 10 in one eye and a placebo lens in the
`fellow eye (N=30); or
`
`